A rare case of acute respiratory distress syndrome secondary to acute lithium intoxication.

Lithium carbonate is a widely administered antimanic drug used for the treatment of bipolar disorder, schizoaffective disorder, and depression. Despite the established clinical efficacy of lithium, its usage must be approached with caution due to its narrow therapeutic index. Lithium poisoning results in multisystem toxicity, and characteristic clinical manifestations are directly correlated to serum lithium concentration. We describe a rather rare but fatal side effect of lithium: acute respiratory distress syndrome (ARDS) in a 46-year-old female on lithium for the treatment of bipolar disease. She was referred for generalized weakness, found in hemodynamic compromise, and had laboratory data significant for a lithium level of 3.3 mmole/L, needing emergent hemodialysis. Subsequently, she developed hypoxic respiratory failure requiring intubation. Her chest x-rays showed new bilateral pulmonary edema, the computed tomography scan showed extensive alveolar consolidation and V/Q scan of low probability for pulmonary embolism. She underwent 3 dialysis sessions and supportive care and was able to be extubated in 5 days. To our knowledge, 4 cases of ARDS after the onset of lithium toxicity have been documented. All patients presented with altered mental status at serum lithium levels ranging from 3.8 to 4.9 mmole/L and cardiogenic etiologies in addition to other likely causes of ARDS were ruled out in each case. The patients were treated with saline hydration (50%) or hemodialysis (50%), indicating that hemodialysis may be a permissive factor in lithium-associated ARDS development rather than a required component. Taken together, we believe that lithium is a likely culprit in the initiation of ARDS and propose the addition of ARDS to the family of clinical manifestations of severe lithium toxicity.

Is depression a chronic mental illness?

Over the past few decades, theory and research on depression have increasingly focused on the recurrent and chronic nature of the disorder. These recurrent and chronic forms of depression are extremely important to study, as they may account for the bulk of the burden associated with the disorder. Paradoxically, however, research focusing on depression as a recurrent condition has generally failed to reveal any useful early indicators of risk for recurrence. We suggest that this present impasse is due to the lack of recognition that depression can also be an acute, time-limited condition. We argue that individuals with acute, single lifetime episodes of depression have been systematically eclipsed from the research agenda, thereby effectively preventing the discovery of factors that may predict who, after experiencing a first lifetime episode of depression, goes on to have a recurrent or chronic clinical course. Greater awareness of the high prevalence of people with a single lifetime episode of depression, and the development of research designs that identify these individuals and allow comparisons with those who have recurrent forms of the disorder, could yield substantial gains in understanding the lifetime pathology of this devastating mental illness.

Diagnostic accuracy of self-collected human papillomavirus specimens as a primary screen for cervical cancer.

The aim of the study was to compare the sensitivity of self-collected with clinician-collected human papillomavirus (HPV) tests and cytology for cervical cancer. A total of 250 non-pregnant, 25-60-year-old women from Leon, Nicaragua, self-collected vaginal specimens for HPV and received a pelvic examination for cytology and reflex HPV. All participants underwent colposcopy and completed questionnaires regarding demographic and medical information. The sensitivities of self-collected brushes, self-collected swabs and clinician-collected HPV tests were 25%, 16.7%, and 16.7%, respectively, with colposcopy as the gold standard and 30%, 22.2% and 40% when cytology was the gold standard. Agreement between self-collection methods was significant (κ=0.84, p<0.001). Although utilisation of colposcopy in every participant resulted in lower sensitivities, the self-collected tests surpassed cytology and significantly agreed with the clinician-collected results. Further clarification of the sensitivity will be required to employ self-collection for cervical cancer screening in low resource areas like rural Nicaragua.

Origin of iridescent colors on the indigo snake.

In the indigo snake, a pattern of undulating lines on the surface of the skin, formed by the junction of rows of cells, acts as a two-dimensional optical diffraction grating to produce the play of colors. The distance between repetitive units of the pattern measured from observations made with an electron microscope are in agreement with those found by spectrometric analysis.

Sex steroid modulation of fatty acid utilization and fatty acid binding protein concentration in rat liver.

The mechanism by which sex steroids influence very low density hepatic lipoprotein triglyceride production has not been fully elucidated. In previous studies we showed that [(14)C]oleate utilization and incorporation into triglycerides were greater in hepatocyte suspensions from adult female rats than from males. The sex differences were not related to activities of the enzymes of triglyceride biosynthesis, whereas fatty acid binding protein (FABP) concentration in liver cytosol was greater in females. These findings suggested that sex differences in lipoprotein could reflect a sex steroid influence on the availability of fatty acids for hepatocellular triglyceride biosynthesis. In the present studies, sex steroid effects on hepatocyte [(14)C]oleate utilization and FABP concentration were investigated directly. Hepatocytes from immature (30-d-old) rats exhibited no sex differences in [(14)C]oleate utilization. With maturation, total [(14)C]oleate utilization and triglyceride biosynthesis increased moderately in female cells and decreased markedly in male cells; the profound sex differences in adults were maximal by age 60 d. Fatty acid oxidation was little affected. Rats were castrated at age 30 d, and received estradiol, testosterone, or no hormone until age 60 d, when hepatocyte [(14)C]oleate utilization was studied. Castration virtually eliminated maturational changes and blunted the sex differences in adults. Estradiol or testosterone largely reproduced the appropriate adult pattern of [(14)C]oleate utilization regardless of the genotypic sex of the treated animal. In immature females and males, total cytosolic FABP concentrations were similar. In 60-d-old animals, there was a striking correlation among all groups (females, males, castrates, and hormone-treated) between mean cytosolic FABP concentration on the one hand, and mean total [(14)C]oleate utilization (r = 0.91) and incorporation into triglycerides (r = 0.94) on the other. In 30-d-old animals rates of [(14)C]oleate utilization were greater, relative to FABP concentrations, than in 60-d-old animals. The sex differences that characterize fatty acid utilization in adult rat hepatocytes are not present in cells from immature animals, and reflect in part the influence of sex steroids. It remains to be determined whether the observed relationship of hepatic FABP concentration to [(14)C]oleate utilization in adult cells is causal or secondary to changes in cellular fatty acid uptake effected through another mechanism. In either case, modulation of triglyceride-rich lipoprotein production by six steroids appears to be mediated to a significant extent by their effects on hepatic fatty acid utilization.

Regulatory perspective on clinical trials and end points for female sexual dysfunction, in particular, hypoactive sexual desire disorder: formulating recommendations in an environment of evolving clinical science.

This article examines the history, current status, and potential future challenges in the development of drugs for female sexual dysfunction (FSD) from the perspective of the United States Food and Drug Administration. In particular, the article focuses on testosterone therapy for hypoactive sexual desire disorder (a component of FSD), and the role of the Division of Reproductive and Urologic Products in facilitating the development of safe and effective therapies for this indication.

Antimicrobial use and bacterial resistance.

The current epidemic of bacterial resistance is attributed, in part, to the overuse of antibiotics. Recent studies have documented increases in resistance with over-use of particular antibiotics and improvements in susceptibility when antibiotic use is controlled. The most effective means of improving use of antibiotics is unknown. Comprehensive management programs directed by multi-disciplinary teams, computer-assisted decision-making, and antibiotic cycling have been beneficial in controlling antibiotic use, decreasing costs without impacting patient outcomes, and possibly decreasing resistance.

Assessment of life events: retrospective vs concurrent strategies.

The relationship of life events to different disorders continues to be of great interest. Most communications, however, have been based on self-report data gathered retrospectively over lengthy intervals (eg, one to ten years). While recent studies have attempted to ascertain the degree of distortion associated with such procedures, none has provided an appropriate basis for estimating absolute decrements of event reporting over time. This study compares the traditional retrospective procedure with a concurrent assessment procedure covering shorter recall periods (one month). The findings indicate as much as 60% of events may be underreported for even the most recent four-month retrospective period. Additionally, particular types of events (eg, desirable events) may be relatively more susceptible to such reporting distortion. Implications of these results for life events assessment and conceptualization of event-disorder associations are discussed.

Failure of cooking to prevent shellfish-associated viral gastroenteritis.

BACKGROUND: In January 1995, Florida experienced the largest outbreak of oyster-associated gastroenteritis ever reported. METHODS: We interviewed both the cohort of persons from 38 gatherings where illness was reported and a sample of harvesters and harvest-area residents. Oysters were traced by means of tags and dealer records, and water quality measures in harvest areas were reviewed. We examined stool specimens for small round structured viruses by means of electron microscopy and amplification of RNA by reverse-transcriptase polymerase chain reaction. We also tested serum specimens for antibodies to Norwalk virus. RESULTS: Of 223 oyster eaters, 58% (129/223) became ill, compared with 3% (2/76) of non-oyster eaters (relative risk, 22; 95% confidence interval, 5.6-87.0). Most oyster eaters (67% [149/223]) ate only cooked (grilled, stewed, or fried) oysters. Oyster eaters who reported eating only thoroughly cooked oysters were as likely to become ill as those who ate raw oysters (relative risk, 0.68; 95% confidence interval, 0.45-1.0; P = .1). In 29 clusters, implicated oysters were from Apalachicola Bay, Florida. A community outbreak occurred in 2 bayside communities before the oyster harvest, leading to an increase in the reportedly common practice of overboard dumping of feces. Small round structured viruses were identified in the stool specimens of 2 harvest-area residents and 9 persons from 8 clusters. Results of water quality tests for fecal coliforms were within acceptable limits. CONCLUSIONS: This large outbreak of gastroenteritis associated with oysters may have resulted from overboard dumping of feces during a community outbreak of diarrheal illness. Our findings of acceptable water quality measures for fecal contamination and the lack of appreciable protective effect from cooking leave the consumer with no assurance of safety.

Prolactin concentrations in the monkey fetus during the last third of gestation.

PRL concentrations were measured in cord plasma obtained at hysterotomy from 26 rhesus monkey fetuses between 111--170 days gestational age (GA). Mean PRL concentrations increased significantly from 23.7 +/- 10.1 (X +/- SE) ng/ml at 121--130 days GA to 126.9 +/- 16.9 ng/ml at 161--170 days GA. A similar significant increase in PRL with age also was observed in samples obtained from 16 fetuses chronically catheterized in utero between 130--155 days GA. Mean PRL levels were 34 +/- 3.2 ng/ml at 131--140 days GA and rose to 82 +/- 9.7 at 150--155 days GA. No difference in PRL concentrations was found between cord blood samples and fetal peripheral blood samples at the ages studied. Maternal PRL levels did not change in samples obtained from chronically catheterized, chair-restrained mothers between 130--155 days GA. A tendency toward an increase in maternal PRL with advancing gestational age was observed in samples collected after hysterotomy. These data indicate that the fetal rhesus monkey demonstrates an increase in plasma PRL similar to that in the human, suggesting a possible physiological role for this hormone in the primate fetus late in gestation.

Conservation of free but not total or non-sex-hormone-binding-globulin-bound testosterone in serum from Nagase analbuminemic rats.

Nagase analbuminemic rats have normal reproductive capacity, normal apparent libido, and normal serum concentrations of LH and FSH. Therefore, it is reasonable to assume that intracellular sex steroid hormone concentrations are normal or at least adequate to maintain normal reproductive function in these rats. To test whether intracellular testosterone concentrations in these rats are maintained by the circulating concentration of free or free-plus-weakly-bound testosterone, we measured the concentrations of total testosterone, free testosterone, and non-sex-hormone-binding-globulin-bound testosterone in sera from five adult male Nagase analbuminemic rats and from five age- and sex-matched controls. We found that the analbuminemic rats had markedly decreased serum concentrations of total and non-sex-hormone-binding-globulin-bound testosterone, but normal serum concentrations of free testosterone. These results suggest that intracellular concentrations of testosterone in biologically relevant organs of the rat are maintained by the concentration of free rather than free-plus-weakly-bound testosterone in plasma, in accord with the free hormone hypothesis.

Use of stool collection kits delivered to patients can improve confirmation of etiology in foodborne disease outbreaks.

BACKGROUND: In 68% of foodborne disease outbreaks, no etiologic pathogen is identified. In two-thirds of outbreaks with no identified etiology, no stool specimens are submitted for testing. METHODS: From April 2001 to March 2003, we pilot-tested use of prepackaged, self-contained stool specimen collection kits in 3 states, delivered to and from patients by courier or mail, to improve rates of specimen collection in the outbreak setting. Specimens were tested for bacterial and viral pathogens at health department laboratories, and results were correlated with epidemiological investigation data. RESULTS: Specimens were returned by > or =1 person in 52 (96%) of 54 outbreaks in which kits were deployed; in total, 263 (76%) of 347 persons who received kits returned specimens. Resolution of symptoms was the most commonly cited reason for nonsubmission of kits. An etiology was confirmed in 37 (71%) of 52 outbreaks with specimens returned; 28 (76%) were attributable to norovirus, and 9 (24%) were attributed to bacterial pathogens. Stool kits were well received and cost an average of approximately 43 dollars per specimen returned. CONCLUSIONS: In two-thirds of foodborne disease outbreaks in which delivered stool collection kits were successfully deployed, an etiologic organism was identified. Delivery of kits to and from patients to improve rates of stool collection in outbreaks in which specimens might otherwise not be submitted could substantially reduce the number of outbreaks with an unknown etiology.

Treatment of hirsutism with a gonadotropin-releasing hormone agonist (nafarelin).

GnRH analogs inhibit the secretion of gonadotropins and, therefore, that of estrogens and androgens of ovarian origin. The purpose of this study was to investigate the use of one superactive agonistic GnRH analog, nafarelin, in the treatment of hirsutism. Six hirsute women were treated with nafarelin (1 000 micrograms/day) for 6 months. An acute rise in serum gonadotropin levels occurred in response to nafarelin administration initially, but it lasted less than 2 weeks. Serum gonadotropin, testosterone, free testosterone, and androstenedione concentrations decreased significantly during treatment. Mean serum LH levels decreased from 17.9 +/- 4.6 (+/- SE) to 5.0 +/- 0.5 mIU/ml (P less than 0.01), and FSH decreased from 9.3 +/- 0.7 to 7.2 +/- 0.9 mIU/ml (P less than 0.05) after 1 month of treatment. The total testosterone concentration fell from 0.77 +/- 0.10 to 0.40 +/- 0.14 ng/ml (P less than 0.01) after 1 month of therapy, and free testosterone decreased from 10.7 +/- 2.7 to 4.1 +/- 1.6 pg/ml (P less than 0.01) after 3 months. Androstenedione levels decreased from 2.4 +/- 0.4 to 1.2 +/- 0.2 ng/ml (P less than 0.01) after 1 month of treatment. The mean concentrations of all of the above hormones remained suppressed throughout treatment. Serum 5 alpha-androstane-3 alpha,17 beta-diol glucuronide levels did not decrease significantly during treatment, nor did dehydroepiandrosterone sulfate levels. The mean estradiol concentration during treatment was 34.8 +/- 3.1 pg/ml. The clinical response was very good; hair growth was slower, and new hair was less coarse compared to the pretreatment period. Hirsutism scores (determined by Ferriman-Gallwey assessment of extent and quality of body hair) improved in four of the six patients. In the six patients, the mean score decreased significantly from 19.3 +/- 3.3 to 13.2 +/- 2.8 (P less than 0.05) at the end of treatment. These data demonstrate that by suppressing ovarian androgen production, nafarelin may be useful for the treatment of hirsutism associated with either increased ovarian androgen production or increased sensitivity of the hair follicle to normal concentrations of circulating androgens.

Variable ovarian response to gonadotropin-releasing hormone antagonist-induced gonadotropin deprivation during different phases of the menstrual cycle.

The gonadotropin dependence of ovarian follicular maturation and corpus luteum function can now be examined in women using antagonistic analogs of GnRH. We studied the responses of three groups of women throughout a control cycle and during the administration of a potent GnRH antagonist, detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] GnRH, Syntex Research). Detirelix (10 mg, sc) was administered for 3 consecutive days during the midfollicular phase (n = 4), preovulatory phase (n = 4), and early luteal phase (n = 4). The pituitary response to detirelix was similar throughout the three phases of the menstrual cycle. Immunoreactive LH concentrations decreased to 35% (mean +/- SEM) of pretreatment values within 8 h after the initial injection and remained suppressed for 72 h after discontinuance of treatment. Immunoreactive FSH concentrations decreased to 73 +/- 3% of pretreatment levels within 8 h and returned to baseline within 24 h after the third injection. In contrast, the ovarian response to detirelix varied markedly during different phases of the cycle. Midfollicular phase treatment was associated with a decline in estradiol (E2) levels from pretreatment values of 246 +/- 48 to 81 +/- 15 pmol/L within 24 h of the last injection. Vaginal bleeding ensued in three of four women. Follicular recruitment was then reinitiated, and an ovulatory LH surge occurred 18.2 +/- 2.9 days after the last injection. Similarly, treatment during the early luteal phase produced a decline in E2 concentrations from 286 +/- 29 to 70 +/- 7 pmol/L and a decline in progesterone concentrations from 20 +/- 1.6 to 1.9 +/- 0.3 nmol/L within 24 h after the last injection. Luteolysis was associated with menstrual bleeding in all four women. The subsequent ovulatory LH surge occurred 16.5 +/- 1.0 days after discontinuance of treatment. In contrast, treatment during the preovulatory phase resulted in a decline in E2 concentrations from 844 +/- 66 to 429 +/- 132 pmol/L during the first 48 h of treatment. Gonadotropin and E2 concentrations subsequently recovered from suppression, growth of the dominant follicle resumed, and a LH surge occurred 5.8 +/- 1.4 days after the last injection. These data indicate that the GnRH antagonist detirelix produces rapid and consistent suppression of pituitary gonadotropin secretion. The magnitude of suppression and preferential suppression of LH vs. FSH are similar throughout the cycle. In contrast, the ovarian response to gonadotropin deprivation varies during the menstrual cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of follicular development by a potent antagonistic analog of gonadotropin-releasing hormone (detirelix).

The ability of a potent long-acting antagonistic analog of GnRH to suppress gonadotropin secretion, disrupt follicular development, and inhibit ovulation was studied in six women with normal menstrual cycles. The GnRH antagonist detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] GnRH; Syntex Research) was administered to six women by sc injection on alternate days during a 27-day period. Six additional women underwent blood sampling only, without receiving detirelix. Within 8 h after the initial injection of detirelix, mean (+/- SEM) serum LH and FSH concentrations decreased by 74 +/- 2% and 26 +/- 3%, respectively. Mean immunoreactive FSH levels, however, returned to baseline after the first 72 h despite continued administration of detirelix. Mean estradiol (E2) concentrations decreased from 165 +/- 15 to 70 +/- 11 pmol/L in the first 24 h. During the treatment period follicular development was inhibited, and none of the six volunteers showed evidence of ovulation, as assessed by serum progesterone (P) levels. Maximal suppression of serum LH and E2 was observed approximately 24 h after each injection of detirelix. Compared to the control volunteers, those receiving detirelix had significantly lower mean serum LH (P less than 0.001), E2 (P less than 0.001), and P (P less than 0.001) levels during treatment; mean FSH concentrations, however, were not statistically different in the treatment and control groups. Rapid recovery of pituitary-ovarian function occurred after completion of treatment. In all six volunteers receiving detirelix, a LH surge occurred 10-16 days after the final injection, followed by increased P levels (greater than 32 nmol/L), indicating ovulation and a luteal phase of normal duration (12-14 days). Detirelix injections elicited local skin reactions (erythema and pruritus), but no systemic side-effects were observed. Thus, this long-acting GnRH antagonist can rapidly suppress gonadotropin secretion, inhibit follicular development, and prevent ovulation.

Dose-dependent inhibition of pituitary-ovarian function during administration of a gonadotropin-releasing hormone agonistic analog (nafarelin).

To determine if treatment with the GnRH agonistic analog nafarelin could reliably block ovulation while only partially disrupting ovarian estrogen production, three degrees of pituitary-ovarian inhibition were investigated. Thirty-two women with ovulatory menstrual cycles were given 125 micrograms (group (Gp) I), 250 micrograms (Gp II), or 1000 micrograms (Gp III) nafarelin daily by intranasal spray. Twenty-seven women completed 6 months of treatment. Basal serum FSH concentrations decreased (P less than 0.01) in all groups. Suppression of serum LH was dose dependent and significant (P less than 0.01) only in Gps II and III. Pituitary desensitization to nafarelin developed in all groups. Peak LH responses to nafarelin decreased by about 70% (Gps I and II) and 95% (Gp III). Basal serum estradiol levels after 1 month of treatment were approximately 70 pg/ml (Gp I) and 25 pg/ml (Gps II and III). Serum estradiol levels increased acutely in Gps I and II, but not in Gp III, in response to each dose of nafarelin. Thus, average daily estradiol levels in Gp II were higher than those in Gp III. Serum testosterone and androstenedione levels decreased slightly (P less than 0.05; Gp II) or by 50% (P less than 0.01; Gp III) during treatment. The effects of nafarelin on ovulatory function also were dose-dependent. In Gp I there were four ovulations (progesterone, greater than 4 ng/ml) and seven instances of luteinization (progesterone, 2-4 ng/ml) during 73 months of nafarelin administration. In contrast, there were no ovulations during 58 and 44 months in Gps II and III, respectively. After discontinuance of nafarelin, ovulatory menstrual function returned rapidly in all women. In summary, inhibition of pituitary-ovarian function by daily intranasal nafarelin administration is dose dependent. Gonadotroph sensitivity to 125 micrograms is variable, and there is inconsistent inhibition of ovulation. Daily doses of 250 or 1000 micrograms analog reliably inhibit ovulation, but are associated with either moderate (Gp II) or marked (Gp III) reduction of ovarian estradiol secretion. The effects of these reduced levels of circulating estradiol on bone are not known. Further investigation, with dosage adjusted according to individual patient sensitivity, may lead to the development of a clinically acceptable contraceptive which consistently inhibits ovulation while maintaining serum estradiol levels sufficient to prevent osteoporosis.

Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (Ganirelix) with minimal histamine-releasing properties: studies in postmenopausal women.

A potent and safe GnRH antagonist has been sought unsuccessfully for the last 2 decades. The recently developed GnRH antagonist RS-26306 or Ganirelix ([N-Ac-D-Nal(2)1,D-pClPhe2,D-Pal(3)3,D-hArg(Et2)6,L-++ +hArg(Et2)8,D-Ala10]GnRH ; Syntex Research, Palo Alto, CA), exhibited high antiovulatory potency and low histamine-releasing properties in preclinical studies. Therefore, we determined the extent to which single sc injections of three doses of RS-26306 (1, 3, and 6 mg) decreased serum concentrations of LH and FSH, the free alpha-subunit of LH/FSH/TSH, PRL, and testosterone in five healthy postmenopausal women. We also examined the pharmacokinetic characteristics of RS-26306 by quantifying serum levels of the drug by RIA. RS-26306 rapidly suppressed serum concentrations of LH, FSH, and free alpha-subunit. RS-26306 (6 mg) maximally decreased serum concentrations (mean +/- SEM) of LH, FSH, and free alpha-subunit by 70.1 +/- 3.6%, 42.3 +/- 2.5%, and 74.6 +/- 3.5%, respectively. RS-26306 also decreased serum testosterone, but not serum PRL, concentrations. RS-26306 concentrations reached peak serum levels at 1.2 +/- 0.3, 1.9 +/- 0.4, and 1.8 +/- 0.5 h, respectively, after 1-, 3-, and 6-mg sc injections. The mean serum half-life values based on the terminal portion of the disappearance curves were 22.8 +/- 2.5 and 26.9 +/- 1.0 h, respectively, after 3- and 6-mg s.c. doses. No systemic side-effects were noted after the administration of RS-26306. Our results demonstrate that the GnRH antagonist RS-26306 has favorable pharmacokinetic characteristics and is a potent suppressor of pituitary gonadotropin secretion in postmenopausal women. These attributes and the lack of systemic side-effects make RS-26306 a promising candidate for future clinical applications.

Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, alpha subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix).

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P less than 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix.(ABSTRACT TRUNCATED AT 400 WORDS)

Stimulation of LH fragments with reduced bioactivity following GnRH agonist administration in women.

In eumenorrheic women with endometriosis and in oligo-amenorrheic women with polycystic ovarian disease (PCO), chronic administration of a long-acting GnRH agonist (GnRH-a) reduced the circulating concentrations of estrogens and androgens to levels similar to those of castrated women. The concommittant elevation of LH in both groups suggested that the measured immunoreactive LH had reduced bioactivity. In seven women with endometriosis, bioactive LH (BA LH) measured as the in-vitro secretion of testosterone by dispersed Leydig cells, was significantly (p less than 0.001) reduced from 10.8 +/- 1.2 (SEM) to 4.4 +/- 0.2 mIU/ml at the end of 28 days of GnRH-a therapy. In five women with PCO, BA LH decreased from 44.2 +/- 15.5 to 5.7 +/- 0.6 mIU/ml (p = 0.06). These changes of BA LH appeared to be responsible for the suppression of ovarian androgen secretion during GnRH-a treatment and in turn may have contributed to the profound decreases of estrogen production by reducing the amount of precursor androgen available for aromatization. Free alpha subunit levels increased simultaneously with the decrease of BA LH at the end of therapy, suggesting a post-receptor effect of GnRH-a. Beta subunit levels became undetectable. Cross-reaction of alpha subunit in the RIA for LH was sufficient to only partially account for the LH levels measured. On sephadex G-100 chromatography the excess immunoreactive material was detected at and immediately following the alpha subunit tracer. Further studies will be necessary to elucidate the chemical nature of the immunoreactive LH secreted during GnRH-a therapy.

Prolactin-secreting adenomas in women. VII. Dopamine regulation of prolactin secretion.

Previous studies demonstrated that high doses of dopamine administered as a constant infusion were capable of suppressing PRL secretion in both normal and hyperprolactinemic individuals. The present study was designed to examine the dose-response relationship of PRL suppression to low doses of dopamine (between 0.06 and 4 micrograms/kg X min) infused in a step-wise fashion. Ten hyperprolactinemic patients with PRL-secreting pituitary adenomas and 10 normally menstruating women in the early follicular phase of a cycle were studied. For hyperprolactinemic women, the mean (+/- SD) serum PRL level (by RIA) was 112 +/- 101 ng/ml, with a range of 26-386 ng/ml, the mean estradiol level (by RIA) was 28 +/- 8 pg/ml, and the mean baseline dopamine level by carboxy-o-methyl transferase assay (COMT) was 357 +/- 237 pg/ml (2.33 +/- 1.54 X 10(-9) M). The normal women had a mean PRL of 8.1 +/- 3.5 ng/ml, a mean estradiol level of 42 +/- 12 pg/ml, and a mean baseline dopamine level of 317 +/- 223 pg/ml (2.07 +/- 1.45 X 10(-9) M). Concentrations of dopamine achieved at the lowest doses infused were less than 10 times baseline levels and were in the nanomolar range. The measured IC50 (the concentration of dopamine required to achieve 50% of maximal suppression) was 6 +/- 3 X 10(-9) M for normal women and 14 +/- 4 X 10(-9) M for hyperprolactinemic patients. The apparent inhibition constant determined by a nonlinear least squares procedure, was 3 +/- 3 X 10(-9) M for normal women and 11 +/- 12 X 10(-9) M for women with hyperprolactinemia. Both groups exhibited dose-dependent suppression of PRL to about 80% of initial values. Under these experimental conditions, the data do not support the hypothesis that there is a marked loss in sensitivity to dopamine in patients with PRL-secreting adenomas.